+

WO2004053192A9 - Formes posologiques administrees oralement de promedicaments analogues de gaba fondu a toxicite reduite - Google Patents

Formes posologiques administrees oralement de promedicaments analogues de gaba fondu a toxicite reduite

Info

Publication number
WO2004053192A9
WO2004053192A9 PCT/US2003/039521 US0339521W WO2004053192A9 WO 2004053192 A9 WO2004053192 A9 WO 2004053192A9 US 0339521 W US0339521 W US 0339521W WO 2004053192 A9 WO2004053192 A9 WO 2004053192A9
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
prodrug
hours
gaba analog
auc
Prior art date
Application number
PCT/US2003/039521
Other languages
English (en)
Other versions
WO2004053192A1 (fr
Inventor
Mark A Gallop
Original Assignee
Xenoport Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xenoport Inc filed Critical Xenoport Inc
Priority to AU2003297909A priority Critical patent/AU2003297909A1/en
Publication of WO2004053192A1 publication Critical patent/WO2004053192A1/fr
Publication of WO2004053192A9 publication Critical patent/WO2004053192A9/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound

Definitions

  • GABA regulates neuronal excitability through binding to specific membrane proteins (i.e., GABAA receptors), which results in opening of an ion channel.
  • GABAA receptors specific membrane proteins
  • the entry of chloride ion through the ion channel leads to hyperpolarization of the recipient cell, which consequently prevents transmission of nerve impulses to other cells.
  • Low levels of GABA have been observed in individuals suffering from epileptic seizures, motion disorders (e.g., multiple sclerosis, action tremors, tardive dyskinesia), panic, anxiety, depression, alcoholism and manic behavior.
  • GABA analogs which have superior pharmaceutical properties in comparison to GABA (e.g., the ability to cross the blood brain barrier). Accordingly, a number of GABA analogs, with considerable pharmaceutical activity have been synthesized in the art (See, e.g., Satzinger et ah, United States Patent No. 4,024,175; Silverman et ah, United States Patent No. 5,563,175; Horwell et ah, United States Patent No. 6,020,370; Silverman et ah, United States Patent No. 6,028,214; Horwell et ah, United States Patent No.
  • GABA analogs including those described above exhibit poor oral absorption across the gut wall.
  • One potential solution to the above problem is converting GABA analogs to prodrugs of GABA analogs (Bryans et ah, International Publication No. WO 01/90052; U.K. Application GB 2,362,646; European Applications EP 1,201,240 and 1,178,034; Yatvin et ah, United States Patent No. 6,024,977; Gallop et ah, United States Patent Application Serial No. 10/171,485, filed June 11, 2002; Gallop et ah, International Publication No. WO 02/28881; Gallop et ah, International Publication No.
  • Acyl by itself or as part of another substituent refers to a radical -C(O)R , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Alkylamino by itself or as part of another substituent refers to a radical -NHR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexyl amino and the like.
  • Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,
  • Carbamoyi by itself or as part of another substituent refers to the radical -C(O)N(R )R where R and R are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl, as defined herein.
  • Carcinogenic potency TDjnT (see Peto et ah, Environmental Health Perspectives 1984, 58, 1-8) is defined for a particular compound in a given animal species as that chronic dose-rate in mg/kg body wt/day which would induce tumors in half the test animals at the end of a standard lifespan for the species. Since the tumor(s) of interest often does occur in control animals, TD 50 is more precisely defined as: that dose-rate in mg/kg body wt/day which, if administered chronically for the standard lifespan of the species, will halve the probability of remaining tumorless throughout that period. A TD 50 can be computed for any particular type of neoplasm, for any particular tissue, or for any combination of these. "Cmax" is the highest drug concentration observed in plasma following an extravascular dose of drug.
  • Compounds used in the invention refers to compounds encompassed by the generic formulae disclosed herein and includes any specific compounds within those formulae whose structure is disclosed herein.
  • the compounds of the invention may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • the compounds of the invention also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes that may be incorporated into the compounds of the invention include, but are not limited to, H, 3 H, 13 C, 14 C, 15 N, 18 O and 17 O.
  • Compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the hydrated, solvated and N-oxide forms are within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms.
  • Cycloheteroalkyl by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
  • Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups.
  • the heteroaryl group is from 5-20 membered heteroaryl, more preferably from 5-10 membered heteroaryl.
  • Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
  • Passive diffusion refers to uptake of an agent that is not mediated by a specific transporter protein.
  • An agent that is substantially incapable of passive diffusion has a permeability across a standard cell monolayer (e.g., Caco-2) in vitro of less than 5 x 10 "6 cm/sec, and usually less than 1 x 10 "6 cm/sec (in the absence of an efflux mechanism).
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. "Patient” includes humans. The terms “human” and “patient” are used interchangeably herein.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Prodrug refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug.
  • a hydroxyl containing drug may be converted to, for example, to a sulfonate, ester or carbonate prodrug, which may be hydrolyzed in vivo to provide the hydroxyl compound.
  • An amino containing drug may be converted, for example, to a carbamate, amide, enamine, imine, N-phosphonyl, N-phosphoryl or N-sulfenyl prodrug, which may be hydrolyzed in vivo to provide the amino compound.
  • a carboxylic acid drug may be converted to an ester (including silyl esters and thioesters), amide or hydrazide prodrug, which be hydrolyzed in vivo to provide the carboxylic acid compound.
  • ester including silyl esters and thioesters
  • amide or hydrazide prodrug which be hydrolyzed in vivo to provide the carboxylic acid compound.
  • Promoiety refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • Transporter protein refers to a protein that has a direct or indirect role in transporting a molecule into and/or through a cell.
  • a transporter protein may be, but is not limited to, solute carrier transporters, co-transporters, counter transporters, uniporters, symporters, antiporters, pumps, equilibrative transporters, concentrative transporters and other proteins, which mediate active transport, energy-dependent transport, facilitated diffusion, exchange mechanisms and specific absorption mechanisms.
  • Transporter proteins may also be, but are not limited to, membrane-bound proteins that recognize a substrate and effect its entry into or exit from a cell by a carrier-mediated transporter or by receptor-mediated transport.
  • prodrug-releasing waxes can be used for oral sustained release administration.
  • suitable sustained prodrug-releasing waxes are disclosed in Cain et ah, United States Patent No. 3,402,240 (carnauba wax, candedilla wax, esparto wax and ouricury wax); Shtohryn et a United States Patent No. 4,820,523 (hydrogenated vegetable oil, bees wax, caranuba wax, paraffin, candelillia, ozokerite and mixtures thereof); and Walters, United States Patent No. 4,421,736 (mixture of paraffin and castor wax).
  • biodegradable polymers comprise a member selected from the group consisting of biodegradable poly(amides), poly (amino acids), poly(esters), poly(lactic acid), poly(glycolic acid), poly(carbohydrate), poly(orthoester), poly (orthocarbonate), poly(acetyl), poly(anhydrides), biodegradable poly(dihydropyrans), and poly(dioxinones) which are known in the art (Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); Heller et ah, United States Patent No. 3,811,444; Michaels, United States Patent No. 3,962,414; Capozza, United States Patent No. 4,066,747; Schmitt, United States Patent No. 4,070,347; Choi et ah, United States Patent No. 4,079,038; Choi et ah, United States Patent No. 4,093,709).
  • An example of providing a dosage form comprises blending a pharmaceutically acceptable carrier like polyethylene glycol, with a known dose of prodrug at an elevated temperature, (e.g., 37 °C), and adding it to a silastic medical grade elastomer with a cross-linking agent, for example, octanoate, followed by casting in a mold. The step is repeated for each optional successive layer. The system is allowed to set for about 1 hour, to provide the dosage form.
  • a pharmaceutically acceptable carrier like polyethylene glycol
  • a known dose of prodrug at an elevated temperature, (e.g., 37 °C)
  • a silastic medical grade elastomer with a cross-linking agent for example, octanoate
  • Representative polymers for manufacturing the dosage form comprise a member selected from the group consisting of olefin, and vinyl polymers, addition polymers, condensation polymers, carbohydrate polymers, and silicone polymers as represented by polyethylene, polypropylene, polyvinyl acetate, polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamide and polysilicone.
  • the polymers and procedures for manufacturing them have been described in the art (Coleman et ah, Polymers 1990, 31, 1187-1231; Roerdink et ah, Drug Carrier Systems 1989, 9, 57-10.; Leong et ah, Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et ah, Handbook of Common Polymers 1971, CRC Press; Chien et ah, United States Patent No. 3,992,518).
  • the dosage form comprises an osmotic dosage form, which comprises a semipermeable wall that surrounds a therapeutic composition comprising the prodrug.
  • the osmotic dosage form comprising a homogenous composition, imbibes fluid through the semipermeable wall into the dosage form in response to the concentration gradient across the semipermeable wall.
  • the therapeutic composition in the dosage form develops osmotic pressure differential that causes the therapeutic composition to be administered through an exit from the dosage form over a prolonged period of time up to 24 hours (or even in some cases up to 30 hours) to provide controlled and sustained prodrug release.
  • the hydrogel layer composition may comprise 10 mg to 1000 mg of a hydrogel such as a member selected from the group consisting of a polyalkylene oxide of 1,000,000 to 8,000,000 which are selected from the group consisting of a polyethylene oxide of 1 ,000,000 weight-average molecular weight, a polyethylene oxide of 2,000,000 molecular weight, a polyethylene oxide of 4,000,000 molecular weight, a polyethylene oxide of 5,000,000 molecular weight, a polyethylene oxide of 7,000,000 molecular weight and a polypropylene oxide of the 1,000,000 to 8,000,000 weight-average molecular weight; or 10 mg to 1000 mg of an alkali carboxymethylcellulose of 10,000 to 6,000,000 weight average molecular weight, such as sodium carboxymethylcellulose or potassium carboxymethylcellulose.
  • a hydrogel such as a member selected from the group consisting of a polyalkylene oxide of 1,000,000 to 8,000,000 which are selected from the group consisting of a polyethylene oxide of 1 ,000,000 weight-average molecular weight, a polyethylene oxide of 2,000,000 molecular weight,
  • the wall comprises 75 wt % (weight percent) to 100 wt % of the cellulosic wall- forming polymer; or, the wall can comprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1 wt % to 25 wt % of a cellulose ether selected from the group consisting of hydroxypropylcellulose or a hydroxypropylalkycellulose such as hydroxypropylmethylcellulose.
  • the total weight percent of all components comprising the wall is equal to 100 wt %.
  • the internal compartment comprises the pro ⁇ rug-containing composition alone or in layered position with an expandable hydrogel composition.
  • the sustained release oral dosage form further provides a concentration of the fused GABA analog in the blood plasma of the patient over time, which curve has an area under the curve (AUC) that is proportional to the dose of the prodrug of fused GABA analog administered, and a maximum concentration C max .
  • the C max is less than 75%, and is preferably, less than 60%, of the C max obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form, and the AUC is substantially the same as the AUC obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form.
  • R 2 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, oxycarbonyl or substituted oxycarbonyl, or optionally, R 2 and R 3 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring
  • compounds of structural Formula (VI) are derived from a fused GABA analog selected from the group consisting of (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, (l ⁇ , 6 ⁇ , 8 ⁇ )-(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, (l ⁇ , 6 ⁇ )-(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid and (l ⁇ , 6 ⁇ , 8 ⁇ )-(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid.
  • R 11 and R 12 are independently hydrogen or methyl.
  • compounds of structural Formula (VIII) are derived from a fused GABA analog selected from the group consisting of (6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((1R, 5R, 6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((IS, 5S, 6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid, ((1R, 5R, 6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid and ((IS, 5S, 6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid.
  • compounds of structural Formula (IX) are derived from a fused GABA analog selected from the group consisting of (7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((1R, 6R, 7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((IS, 6S, 7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid, ((1R, 6R, 7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid and ((IS, 6S, 7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid.
  • the present invention provides compounds of structural Formula (X):
  • R is selected from the group consisting of aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl. More preferably, R 2 is selected from the group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl and 3-mdolylmethyl.
  • R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl or substituted heteroaryl. More preferably, R 4 and R 5 are independently hydrogen, alkyl, alkoxycarbonyl, aryl, arylalkyl or heteroaryl.
  • R 4 and R 5 are independently hydrogen, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, 3-pyridyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl.
  • R 6 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl or substituted heteroaryl.
  • R 6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1 -dimethoxyethyl, 1 , 1 -diethoxyethyl, 1 -( 1 ,3-dioxolan-2-yl)-ethyl, 1 -(1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, l-(l,3-dioxolan-2-yl)-propyl, l-(l,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1 , 1 -diethoxybutyl, 1 -( 1 ,3 -di
  • each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently hydrogen, alkyl or substituted alkyl. More preferably, each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently hydrogen or methyl.
  • R 1 is hydrogen and R 2 and R 3 together with the atoms to which they are attached form a pyrrolidine ring.
  • R 1 is hydrogen.
  • R 3 is hydrogen and R 2 is selected from the group consisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 4-imidazolylmethyl, 3-indolylmethyl, -CH 2 OH, -CH(OH)CH 3 , -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 SCH 3 , -CH 2 SH, -CH 2 (CH 2 ) 3 NH 2 and -CH 2 CH 2 CH 2 NHC(NH)NH 2 .
  • R 1 is hydrogen.
  • R 1 is methyl, ethyl, benzyl, -C(CH 3
  • R 4 is methyl
  • R 1 and R 5 are hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1 -dimethoxyethyl, 1 , 1 -diethoxyethyl, 1 -( 1 ,3-dioxolan-2-yl)-ethyl, 1 -( 1 ,3 -dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, 1 -(1 ,3-dioxolan-2-yl)-propyl, 1 -(1 ,3-dioxan-2-yl)-propyl, 1 -(1 ,3-d
  • R 4 is isopropyl
  • R 1 and R 5 are hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1 -dimethoxyethyl, 1,1 -diethoxyethyl, l-(l,3-dioxolan-2-yl)-ethyl, l-(l,3-dioxan-2-yl)-ethyl, 1,1 -dimethoxypropyl, 1,1 -diethoxypropyl, 1 -( 1 ,3-dioxolan-2-yl)-propyl, 1 -( 1 ,3-dioxan-2-yl)-propyl, 1 ,
  • 1 -(1 ,3-dioxan-2-yl)-benzyl 1 , 1 -dimethoxy-2-phenethyl, 1 , 1 -diethoxy-2-phenethyl, l-(l,3-dioxolan-2-yl)-2-phenethyl, l-(l,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl.
  • R 4 is phenyl
  • R 1 and R 5 are hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1 -dimethoxyethyl, 1 , 1 -diethoxyethyl, 1 -(1 ,3-dioxolan-2-yl)-ethyl, 1 -( 1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, 1 -(1 ,3-dioxolan-2-yl)-propyl, 1 -(1 ,3-dioxan-2-yl)-propyl, 1 -(1 ,3-
  • R 4 is isopropoxycarbonyl
  • R 5 is methyl
  • R 1 is hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1 -dimethoxyethyl, 1,1 -diethoxyethyl, l-(l,3-dioxolan-2-yl)-ethyl, 1 -(1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, 1 -(1 ,3 -dioxolan-2-yl)-propyl, 1 -(1 ,3 -dioxan-2
  • R 4 is butoxycarbonyl
  • R 5 is methyl
  • R 1 is hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1 -dimethoxyethyl, 1 , 1 -diethoxyethyl, 1 -( 1 ,3 -dioxolan-2-yl)-ethyl, 1 -(1 ,3-dioxan-2-yl)-ethyl, 1 ,1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, 1 -( 1 ,3-dioxolan-2-yl)-propyl, 1 -(1 ,3-dioxxolan-2-yl)-propyl, 1
  • R 4 is tert-butoxycarbonyl
  • R 5 is methyl
  • R 1 is hydrogen
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1 -dimethoxyethyl, 1,1 -diethoxyethyl, l-(l,3-dioxolan-2-yl)-ethyl, 1 -( 1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, l-(l,3-dioxolan-2-yl)-propyl, l-(l,3-dioxan-2-yyl)-propyl, l-(l,
  • R 4 is cyclohexyloxycarbonyl
  • R is methyl
  • R is hydrogen
  • R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1 -dimethoxyethyl, 1,1 -diethoxyethyl, l-(l,3-dioxolan-2-yl)-ethyl, 1-(1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, l-(l,3-dioxolan-2-yl)-propyl, l-(l,3-dioxan-2-yl)-propyl, l-(l,3-di
  • each of R 1 , R 4 and R 5 is hydrogen, and R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1 -dimethoxyethyl, 1 , 1 -diethoxyethyl, 1 -(1 ,3-dioxolan-2-yl)-ethyl, 1 -(1 ,3-dioxan-2-yl)-ethyl, 1 , 1 -dimethoxypropyl, 1 , 1 -diethoxypropyl, 1 -( 1 ,3 -dioxolan-2-yl)-propyl, 1 -(1 ,3-dioxan-2-yl)-propyl, 1 -(1 ,3-dioxan
  • the dosage forms of the invention maybe admimstered as a preventative measure to a patient having a predisposition for epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially, neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome.
  • the dosage forms of the invention may be used for the prevention of one disease or disorder and concurrently treating another (e.g., prevention of psychosis while treating gastrointestinal disorders; prevention of neuropathic pain while treating ethanol withdrawal syndrome).
  • the suitability of the dosage forms of the invention in treating epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders hot flashes, restless legs syndrome, urinary incontinence and ethanol withdrawal syndrome may be determined by methods described in the art (See, e.g., Satzinger et ah, United States Patent No. 4,024,175; Satzinger et ah, United States Patent No. 4,087,544; Woodruff, United States Patent No. 5,084,169; Silverman et al, United States Patent No.
  • the dosage forms of the invention When used to treat or prevent the above disease or disorders the dosage forms of the invention may be administered or applied singly, or in combination with other agents.
  • the dosage forms of the invention may also deliver a fused GABA analog prodrug in combination with another pharmaceutically active agent, including another fused GABA analog prodrug.
  • the dosage forms of the invention upon releasing the fused GABA analog prodrug, preferably provide fused GABA analogs upon in vivo administration to a patient.
  • the promoiety or promoieties of the prodrug may be cleaved either chemically and/or enzymatically.
  • One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any other suitable tissue of a mammal may enzymatically cleave the promoiety or promoieties of the prodrug. The mechanism of cleavage is not important to the current invention.
  • the promoiety or promoieties may be cleaved prior to absorption by the gastrointestinal tract (e.g., within the stomach or intestinal lumen) and/or after absorption by the gastrointestinal tract (e.g., in intestinal tissue, blood, liver or other suitable tissue of a mammal). If the promoiety or promoieties are cleaved prior to absorption by the gastrointestinal tract, the resulting fused GABA analogs may be absorbed into the systemic circulation conventionally (e.g., via an amino acid transporter located in the small intestine). If the promoiety or promoieties are cleaved after absorption by the gastrointestinal tract, these fused GABA analog prodrugs may have the opportunity to be absorbed into the systemic circulation either by passive diffusion, active transport or by both passive and active processes.
  • the present pharmaceutical compositions contain a therapeutically effective amount of one or more fused GABA analog prodrugs, preferably in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle, so as to provide the form for proper administration to a patient.
  • the prodrug and pharmaceutically acceptable vehicles are preferably sterile.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present pharmaceutical compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • the extended release oral dosage forms of fused GABA analog prodrugs are administered to treat or prevent diseases or disorders such as epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome.
  • diseases or disorders such as epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, hot flashes, restless legs syndrome, urinary incontinence or ethanol withdrawal syndrome.
  • the amount of fused GABA analog prodrug that will be effective in the treatment of a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques known in the art as previously described, h addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges.
  • the amount of a prodrug administered will, of course, be dependent on, among other factors, the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the dosage forms of the invention are adapted to be administered to a patient no more than twice per day, more preferably, only once per day. Dosing may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease state or disorder.
  • Suitable dosage ranges for oral administration are dependent on the potency of the parent fused GABA analog, but are generally between about 0.001 mg to about 200 mg of a compound of the invention per kilogram body weight.
  • Other fused GABA analogs may be more potent and lower doses may be appropriate for both the parent drug and any prodrug (measured on an equivalent molar basis). Dosage ranges may be readily determined by methods known to the skilled artisan.
  • the prodrugs used in the invention are preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans.
  • in vitro assays can be used to determine whether administration of a specific prodrug or a combination of prodrugs is preferred for reducing convulsion.
  • the prodrugs may also be demonstrated to be effective and safe using animal model systems.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une forme posologique à libération prolongée des analogues de GABA fondu ayant une toxicité réduite. Les formes posologiques sont particulièrement utiles pour administrer ces analogues de GABA fusionnés qui sont métabolisés pour former un aldéhyde. Les formes posologiques de l'invention sont utiles dans le traitement ou la prévention de maladies et/ou de troubles pour lesquels on connaît l'efficacité thérapeutique des analogues de GABA fondu.
PCT/US2003/039521 2002-12-11 2003-12-11 Formes posologiques administrees oralement de promedicaments analogues de gaba fondu a toxicite reduite WO2004053192A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003297909A AU2003297909A1 (en) 2002-12-11 2003-12-11 Orally administered dosage forms of fused gaba analog prodrugs having reduced toxicity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US43293102P 2002-12-11 2002-12-11
US60/432,931 2002-12-11
US43324302P 2002-12-12 2002-12-12
US60/433,243 2002-12-12

Publications (2)

Publication Number Publication Date
WO2004053192A1 WO2004053192A1 (fr) 2004-06-24
WO2004053192A9 true WO2004053192A9 (fr) 2004-11-04

Family

ID=32511679

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/039521 WO2004053192A1 (fr) 2002-12-11 2003-12-11 Formes posologiques administrees oralement de promedicaments analogues de gaba fondu a toxicite reduite

Country Status (3)

Country Link
US (1) US20040162351A1 (fr)
AU (1) AU2003297909A1 (fr)
WO (1) WO2004053192A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700652B2 (en) 2003-09-11 2010-04-20 Xenoport, Inc. Treating urinary incontinence using prodrugs of GABA analogs

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2996431A (en) * 1953-12-16 1961-08-15 Barry Richard Henry Friable tablet and process for manufacturing same
US3402240A (en) * 1957-06-25 1968-09-17 Pfizer & Co C Medicinal tablet and process of making same
US3139383A (en) * 1961-06-26 1964-06-30 Norton Co Encapsulated time release pellets and method for encapsulating the same
US3962414A (en) * 1972-04-27 1976-06-08 Alza Corporation Structured bioerodible drug delivery device
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3811444A (en) * 1972-12-27 1974-05-21 Alza Corp Bioerodible ocular device
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
DE2336218C3 (de) * 1973-07-17 1985-11-14 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Orale Arzneiform
US3992518A (en) * 1974-10-24 1976-11-16 G. D. Searle & Co. Method for making a microsealed delivery device
GB1478759A (en) * 1974-11-18 1977-07-06 Alza Corp Process for forming outlet passageways in pills using a laser
US4087544A (en) * 1974-12-21 1978-05-02 Warner-Lambert Company Treatment of cranial dysfunctions using novel cyclic amino acids
DE2460891C2 (de) * 1974-12-21 1982-09-23 Gödecke AG, 1000 Berlin 1-Aminomethyl-1-cycloalkanessigsäuren und deren Ester, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
US4093709A (en) * 1975-01-28 1978-06-06 Alza Corporation Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)
US4063064A (en) * 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
US4079038A (en) * 1976-03-05 1978-03-14 Alza Corporation Poly(carbonates)
US4066747A (en) * 1976-04-08 1978-01-03 Alza Corporation Polymeric orthoesters housing beneficial drug for controlled release therefrom
US4070347A (en) * 1976-08-16 1978-01-24 Alza Corporation Poly(orthoester) co- and homopolymers and poly(orthocarbonate) co- and homopolymers having carbonyloxy functionality
US4285987A (en) * 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
US4434153A (en) * 1982-03-22 1984-02-28 Alza Corporation Drug delivery system comprising a reservoir containing a plurality of tiny pills
US4421736A (en) * 1982-05-20 1983-12-20 Merrel Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
US4721613A (en) * 1982-12-13 1988-01-26 Alza Corporation Delivery system comprising means for shielding a multiplicity of reservoirs in selected environment of use
US4820523A (en) * 1986-04-15 1989-04-11 Warner-Lambert Company Pharmaceutical composition
US4752470A (en) * 1986-11-24 1988-06-21 Mehta Atul M Controlled release indomethacin
US4816263A (en) * 1987-10-02 1989-03-28 Alza Corporation Dosage form for treating cardiovascular diseases comprising isradipine
US4853229A (en) * 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
US5084479A (en) * 1990-01-02 1992-01-28 Warner-Lambert Company Novel methods for treating neurodegenerative diseases
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6197819B1 (en) * 1990-11-27 2001-03-06 Northwestern University Gamma amino butyric acid analogs and optical isomers
NZ331142A (en) * 1996-03-14 2001-04-27 Warner Lambert Co Bridged cyclic amino acids as pharmaceutical agents
GEP20012413B (en) * 1996-03-14 2001-04-25 Warner Lambert Co Novel Substituted Cyclic Amino Acids as Pharmaceutical Agents
USRE41920E1 (en) * 1996-07-24 2010-11-09 Warner-Lambert Company Llc Isobutylgaba and its derivatives for the treatment of pain
US6375987B1 (en) * 1996-10-01 2002-04-23 Gattefossé, S.A. Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix
FR2779651B1 (fr) * 1998-06-16 2001-04-20 Gattefosse Ets Sa Procede pour la fabrication de comprimes a liberation prolongee de principe(s) actif(s) presentant une cinetique de dissolution d'ordre zero
US6171615B1 (en) * 1998-07-06 2001-01-09 Gattefoss{acute over (e)} Sustained release theophylline formulations, excipient systems and methods of production
BR0208922A (pt) * 2001-04-19 2004-04-20 Warner Lambert Co Aminoácidos bicìclicos ou tricìclicos fundidos
GB2375109A (en) * 2001-05-04 2002-11-06 Warner Lambert Co Process for preparing bicyclic amino acid
ES2296956T5 (es) * 2001-06-11 2011-07-12 Xenoport, Inc. Profármacos de análogos de gaba, composiciones y sus usos.
US7186855B2 (en) * 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6818787B2 (en) * 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
EP1485082A4 (fr) * 2002-02-19 2009-12-30 Xenoport Inc Procede de synthese de promedicaments a partir de derives de 1-acyl-alkyl et compositions correspondantes
AU2003222033A1 (en) * 2002-03-20 2003-10-08 Xenoport Cyclic 1-(acyloxy)-alkyl prodrugs of gaba analogs, compositions and uses thereof

Also Published As

Publication number Publication date
AU2003297909A8 (en) 2004-06-30
AU2003297909A1 (en) 2004-06-30
WO2004053192A1 (fr) 2004-06-24
US20040162351A1 (en) 2004-08-19

Similar Documents

Publication Publication Date Title
AU2002310409B2 (en) Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
AU2002310409A1 (en) Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
AU2007267510B2 (en) Controlled release of phenolic opioids
WO2007027477A2 (fr) Traitement de la vulvodynie utilisant des prodrogues d'analogues du gaba
CA2538802C (fr) Traitement ou prevention du syndrome des jambes sans repos a l'aide de promedicaments a base d'analogues du gaba
WO2005019163A2 (fr) Prodrogues a base de carbamate d'alkyle acyle, procede de synthese et utilisation
WO2005025562A1 (fr) Traitement et/ou prevention de l'incontinence urinaire et promedicaments des analogues gaba
NZ543138A (en) Treating or preventing hot flashes using prodrugs of GABA analogs
US20070049626A1 (en) Treating premature ejaculation using gabapentin and pregabalin prodrugs
NO335606B1 (no) Acyloksyalkyl karbamatforbindelser, anvendelse derav, samt mellomprodukter for fremstilling av disse
WO2004052360A1 (fr) Promedicaments d'analogues gaba fusionnes, compositions pharmaceutiques, et utilisations correspondantes
WO2004053192A9 (fr) Formes posologiques administrees oralement de promedicaments analogues de gaba fondu a toxicite reduite
AU2013202270B2 (en) Controlled release of phenolic opioids
NZ582209A (en) Acyloxyalkyl carbamate prodrugs, methods of synthesis and use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
COP Corrected version of pamphlet

Free format text: PUBLISHED INTERNATIONAL SEARCH REPORT (3 PAGES), REPLACED BY CORRECT INTERNATIONAL SEARCH REPORT (1PAGE)

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载